After a decline in rates of infection over several decades, a disturbing increase in the incidence of tuberculosis (TB) is occurring. Because TB is highly contagious it poses a profound threat to public health. TB bacteria are easily passed from person to person in airborne droplets formed when a person with active TB sneezes or coughs.
Even more alarming has been the rise of multidrug-resistant tuberculosis (MDRTB). Prior to 1984, about 10% of TB bacteria isolated from patients in the United States were resistant to even a single antibacterial drug. In 1984, 52% of patients were infected with Mycobacterium tuberculosis (also referred to as tubercle bacilli) resistant to at least one drug, and 32% were resistant to one or more drugs. Outbreaks of MDRTB have been reported in 13 states. Ten percent of the recorded MDRTB cases to date have occurred in previously healthy people whose mortality rate--70 to 90%--has been nearly the same as that of immunosuppressed persons with MDRTB (Snider and Roper, 1992).
The United States Centers for Disease Control (CDC) has released preliminary results of a joint study with the New York State Health Department showing that cases of drug-resistant TB have more than doubled since 1984. CDC data from the first quarter of 1991 show that many of these drug-resistant strains are resistant to both of the frontline TB drugs, rifampin and isoniazid. Outbreaks of MDRTB have occurred in hospitals in Miami and New York City, as well as in the New York State prison system. In one hospital in New York City, the median interval between diagnosis of MDRTB and death was only four weeks. Additional clusters of MDRTB were reported to the CDC in 1990 and 1991 from Mississippi, Missouri, and Michigan.
There are five frontline drugs known to be highly effective against Mycobacterium tuberculosis and five second-line drugs that can be used when resistance to one or more of the frontline drugs is detected. Ironically, in the United States, until April 1992, there were shortages of antituberculosis drugs, some of which are crucially needed when resistance to the frontline drugs rifampin and isoniazid is present. These shortages had occurred because several pharmaceutical companies had ceased production of these drugs.
Because of its persistence in the body, the tubercle bacillus is a notoriously difficult pathogen to control. Although bacille Calmette-Guerin (BCG) vaccine protects against severe tuberculosis meningitis and disseminated TB in children, its efficacy against pulmonary TB in adults has varied widely in different parts of the world. Treatment of conventional TB is effective, but expensive, requiring daily treatment with multiple drugs for a minimum of six months. There is a common tendency among TB patients to stop taking their drugs when the drugs begin to have their beneficial effect or to take the medications only intermittently. When this happens, relapses are frequent and very often are caused by drug-resistant tubercle bacilli that have survived the initial course of treatment. The emergence of drug-resistant M. tuberculosis is in many ways an index of individual compliance with antituberculosis chemotherapy and of the inability of the health care infrastructure to ensure adequate treatment. Many public health agencies that once could play key roles in this process have had their budgets cut drastically in recent years and hence are unable to perform this crucial service.
MDRTB is extraordinarily difficult to treat, and a majority of patients do not respond to therapy. Total treatment costs for an individual with MDRTB can be as much as ten times the cost of traditional treatment; the cost of the treatment drugs alone can be as much as 21 times as great.
The preferred treatment for classical TB consists of isoniazid, rifampin, and pyrazinamide. For patients whose tubercle bacilli are thought to be resistant to isoniazid, a fourth drug, ethambutol, is commonly added to the regimen until drug susceptibility results are known. Isolates of tubercle bacilli resistant to both isoniazid and rifampin, now representing about 20% in some cities, require specialized treatment with additional medications, which may include streptomycin and ciprofloxacin for almost two years.
The tubercle bacillus is a slow-growing organism. Three to six weeks are needed to grow the bacteria in the clinical laboratory, and an additional three to six weeks are needed to screen for antibiotic resistance. Such extended laboratory procedures can result in a delay in diagnosis, which means that patients with unrecognized drug-resistant TB may be treated ineffectively and remain infectious for a longer period. In HIV-positive individuals, MDRTB usually causes death within 4 to 16 weeks after being diagnosed, which is often before laboratory tests on drug susceptibility and resistance can be completed.
There is no evidence that mutation rates in M. tuberculosis organisms have increased or that increased virulence is to blame for the recent deadly outbreaks of TB. It is likely that drug-resistant forms of tuberculosis arose because of patient noncompliance with the 6- to 12-month regimen of antibiotics required to treat TB. Ineffective treatment regimens also play a role in the rising incidence of TB. To address noncompliance, some states with high TB rates are considering approaches to outreach, such as expanding directly observed therapy (DOT); others may reestablish inpatient facilities similar to the TB sanatoria of the first half of this century. Standard treatment regimens for TB have also been updated. Instead of taking two or three antibiotics, TB patients now take four. Still, as noted earlier, the current shortages of antituberculosis drugs in the United States have made even standard treatment difficult.
A series of nitroimidazo[2,1-b]oxazole dedvates was described in Sehgal, K. et al., "Novel Nitroimidazo[2,1-b]oxazole Formation from Reaction of 2,4(5)-Dinitroimidazole with Oxiranes (1)," J. Heterocyuclic Chem. 16:1499-1500 (1979). Compounds of this type have the following general formula (I): ##STR3## These compounds were described as potential radiosensitizing agents for use in the radiotherapy of cancer (Agrawal, K. et al., "Potential Radiosensitizing Agents. Dinitroimidazoles," J. Med Chem. 22(5):583-586 (1979); Sehgal, R. et al, "Potential Radiosensitizing Agents. 2. Synthesis and Biological Activity of Derivatives of Dinitroirnidazole with Oxiranes,"J. Med. Chem. 24:601-604 (1981). More recently, certain nitroimidazole compounds were reported to exhibit antimicrobial properties, including antitubercular activity (see, e.g., Nagarajan, K. et al., "Nitroimidazoles XXI. 2,3-dihydro-6-nitroimidazo [2. 1-b]oxazoles with antitubercular activity," Eur. J. Med Chem. 24:631-633 (1989). In addition, the compound of formula (I) in which R is ethyl (2-ethyl-5-nitro-2,3-dihydro[2,1-b]imidazo-oxazole, also known as Ceiby-Geigy CGI 17341) has recently been shown to exhibit activity against Mycobacterium tuberculosis (Ashtekar, D. et al, "In Vitro and In Vivo Activities of the Nitroimidazole CGI 17341 against Mycobacterium tuberculosis," Antimicrobial Agents and Chemotherapy, 37(2):183-186 (1993).
Pseudomembranous colitis (PMC) is a serious intestinal disease marked by severe colonic intimation, diarrhea, abdominal cramps, and mucosal plaques or pseudomembranes. PMC is caused by the over production of toxigenic Clostridium difficile in the gut. C. difficile is a spore-forming anaerobe and is the major nosocomial pathogen of PMC. The over growth of C. difficile occurs when the bacterial flora of the GI tract has been modified due to extensive use of broad spectrum antibiotics. Two toxins, A and B, are produced by C. difficile. The toxins attack membranes or microfilaments of colon cells producing inflamation and necrosis. Toxin A causes intestinal hemorrhage and fluid secretion while toxin B is cytotoxic.
PMC as a subclass of diarrheal disease has become a frequent complication of antibiotic use. PMC normally appears 5-10 days after onset of antibiotic therapy. A watery diarrhea is the most common symptom, occuring in 90-95% of all PMC cases (B. Aronsson et al. J. Infect. Dis. 151:476-481 (1985)). Sever cases of PMC can cause high fever, leukocytosis, dehydration, electrolyte imbalance, and death (see Clostridium difficle: Its role in Intestinal Disease. Ed. R. D. Kolfe and S. M. Finegold, Academic Press Inc., New York, 1988 and R. Fekety, OAntibiotic-Associated Colitis. Mediguide to Infectious DiseaseO Vol 4, pp 1-7, 1984).
Patients at greatest risk include the eldery, debilitated cancer patients, and patients undergoing abdominal surgery. Untreated C. difficile produces 10-20% mortality in elderly or chronically debilitated patients (G. M. Dosik et al., Am. J. Med. 67:646-656 (1979)). Worldwide incidence of PMC is unknown due to the lack of appropriate studies. However, in industrialized countries, C. difficile is rapidly becoming the most common enteric bacterial pathogen after Campylobacter and Salmonella (J. Bartlett, see Clostridium difficle: Its role in Intestinal Disease. Ed. R. D. Rolfe and S. M. Finegold, Academic Press Inc., New York, 1988 pp. 1-13).
Antibiotics most frequently used to treat PMC include vancomycin, metronidazole, and bacitracin. Vancomycin is a very expensive treatment, $100-400 for a ten day course. Relapse rate after vancomycin therapy has been shown in experimental animals (B. Swannson et. al, Antimicrobial Agents and Chemotherapy, 35:1108-1111 (1991) and J. G. Bartlett et al., Clin. Infect. Dis. (S4) S265-72 (1994)). Due to the increase of vancomycin resistant bacteria, the use of vancomycin for C. difficile infections may be on the decline. Metronidazole is less effective than vancomycin, however, its also less expensive. Metronidazole is orally absorbed and may expose patients to potential side effects that are associated with the drug (PHYSICIANS DESK REFERENCE, 48TH EDITION, 1994, pp- 1704-1706). Metronidazole has a relapse rate similar to vancomycin. Bacitracin is a antibiotic polypeptide and is commerically available as a mixture of nine peptides. It is also expensive and no convenient oral dosage form is available.
A need continues in the art, however, for improved agents that exhibit antimicrobial activity against pathogenic mycobacteria, and more particularly for agents and their derivatives that may be highly useful in the treatment of MDRTB.